DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Epidemiological profile and north-south gradient driving baseline systemic involvement of primary Sjögren's syndrome.

OBJECTIVE: To characterize the systemic phenotype of primary Sjögren's syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores. METHODS: The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren's syndrome from the five continents. RESULTS: The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available. At diagnosis, the mean total ESSDAI score was 6.1; 81.8% of patients had systemic activity (ESSDAI score ≥1). Males had a higher mean ESSDAI (8.1 vs 6.0, P < 0.001) compared with females, as did patients diagnosed at <35 years (6.7 vs 5.6 in patients diagnosed at >65 years, P < 0.001). The highest global ESSDAI score was reported in Black/African Americans, followed by White, Asian and Hispanic patients (6.7, 6.5, 5.4 and 4.8, respectively; P < 0.001). The frequency of involvement of each systemic organ also differed between ethnic groups, with Black/African American patients showing the highest frequencies in the lymphadenopathy, articular, peripheral nervous system, CNS and biological domains, White patients in the glandular, cutaneous and muscular domains, Asian patients in the pulmonary, renal and haematological domains and Hispanic patients in the constitutional domain. Systemic activity measured by the ESSDAI, clinical ESSDAI (clinESSDAI) and disease activity states was higher in patients from southern countries (P < 0.001). CONCLUSION: The systemic phenotype of primary Sjögren's syndrome is strongly influenced by personal determinants such as age, gender, ethnicity and place of residence, which are key geoepidemiological players in driving the expression of systemic disease at diagnosis.

Venous thrombosis and relapses in patients with Behçet's disease. Descriptive analysis from Spanish network of Behçet's disease (REGEB cohort).

OBJECTIVES: To describe the characteristics of patients with Behçet's disease (BD) who presented with venous thrombosis. In addition, we identified the factors associated with this venous involvement and those related with recurrent venous thrombosis. METHODS: Up to January 2015, 544 BD patients from 20 Spanish hospitals had been included in the REGEB (REGistro de la Enfermedad de Behçet as Spanish nomenclature). We selected those patients who presented venous thrombosis. Descriptive analysis was performed and factors related with venous thrombosis were identified. RESULTS: Overall, 99 (18.2%) BD patients had vascular thrombosis, 91 (16.7%) of them (16.7%) involving venous vessels and 18 (19.7%) suffered from venous thrombotic relapse. Lower limbs were the most common location of deep venous thrombosis present in up to 60% of patients. In 12 (13.2%) patients, venous thrombosis affected two vascular territories simultaneously and in 6 (6.6%) the venous and arterial involvement coincided in time. Overall, at the diagnosis of venous thrombosis, 97.6% of patients presented concomitantly other clinical symptoms attributable to BD. In logistic regression multivariate analysis factors associated to venous thrombosis were male sex (Odds ratio [OR] 4.3, 95% confidence interval [CI] 2.5-7.7), erythema nodosum (OR 2.4, 95%CI 1.4-4.1), fever (OR 2.0, 95%CI 1.1-3.8), and central nervous system (CNS) involvement (OR 2.5, 95%CI 1.3-4.8). Considering relapses, CNS involvement was an independent risk factor according logistic regression. However, Cox multivariate analysis did not confirm this finding. CONCLUSIONS: We identified factors related with venous involvement in patients included in the REGEB cohort.

Severe, life-threatening phenotype of primary Sjögren's syndrome: clinical characterisation and outcomes in 1580 patients (GEAS-SS Registry).

OBJECTIVES: To analyse the clinical features and outcomes of patients presenting with life-threatening systemic disease in a large cohort of Spanish patients with primary Sjögren's syndrome (SS). METHODS: The GEAS-SS multicentre registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS, and included more than 20 Spanish reference centres with substantial experience in the management of SS patients. By January 2018, the database included 1580 consecutive patients fulfilling the 2002 classification criteria for primary SS. Severe, life-threatening systemic disease was defined as an activity level scored as "high" in at least one ESSDAI domain. RESULTS: Among 1580 patients, 208 (13%) were classified as presenting a severe, potentially life-threatening systemic disease: 193 presented one ESSDAI domain classified as high, 14 presented two high scored domains and only one presented three high activity domains. The ESSDAI domains involved consisted of lymphadenopathy in 78 (37%) cases, CNS in 28 (13%), PNS in 25 (12%), pulmonary in 25 (12%), renal in 21 (10%), cutaneous in 19 (9%), articular in 18 (9%), haematological in 7 (3%) and muscular in 4 (2%). Patients with severe systemic disease were more frequently men (p=0.001) and had a higher frequency of anaemia (p<0.001), lymphopenia (p<0.001), rheumatoid factor (p=0.021), low C3 levels (p=0.015), low C4 levels (p<0.001) and cryoglobulins (p<0.001). From a therapeutic point of view, systemic patients received more frequently glucocorticoids (p<0.001), immunosuppressants (p<0.001), intravenous immunoglobulins (p=0.008) and rituximab (p<0.001). We found an overall mortality rate of 20% in severe systemic patients, a rate that reached to 33% in patients presenting two or more high systemic involvements; these patients had a higher frequency of low C4 levels (p=0.012) and cryoglobulins (p=0.001) in comparison with those with a single severe organ involved. CONCLUSIONS: 13% of patients with primary SS develop a potentially life-threatening systemic disease (mainly lymphoma, but also severe internal organ involvements including nervous system, the lungs and the kidneys). This subset of patients requires intensive therapeutic management with a mortality rate of nearly 20% of cases.

How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project).

OBJECTIVES: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS). METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays. RESULTS: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESS- DAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains). CONCLUSIONS: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.

Influence of geolocation and ethnicity on the phenotypic expression of primary Sjögren's syndrome at diagnosis in 8310 patients: a cross-sectional study from the Big Data Sjögren Project Consortium.

OBJECTIVES: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed. RESULTS: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69). CONCLUSIONS: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry).

OBJECTIVE: To evaluate systemic involvement in primary SS in a large cohort of Spanish patients using the EULAR-SS disease activity index (ESSDAI) definitions. METHODS: Systemic involvement was characterized using ESSDAI definitions for the 10 clinical domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system and muscular). ESSDAI scores at diagnosis, during follow-up and cumulated at the last visit were calculated. RESULTS: The cohort consisted of 921 patients. After a mean follow-up of 75 months, 77 (8%) patients still had an ESSDAI score of zero at the last visit. Organ by organ, the percentage of patients who developed activity during the follow-up (ESSDAI score ≥ 1 at any time) ranged between 1.4% and 56%, with articular, pulmonary and peripheral neurological involvement being the most common. Logistic multivariate regression analysis showed the following features at diagnosis and had the closest association with systemic activity (statistically significant independent variables in at least two domains): cryoglobulinaemia in five domains; anaemia, lymphopenia and low C3 levels in three domains each and age <35 years in two domains. Sicca features, ANA and RF at diagnosis were not associated with a higher cumulated activity score in any clinical domain. CONCLUSION: Primary SS is undeniably a systemic disease, with the joints, lungs, skin and peripheral nerves being the most frequently involved organs. Cytopenias, hypocomplementaemia and cryoglobulinaemia at diagnosis strongly correlated with higher cumulated ESSDAI scores in the clinical domains. Clinically the ESSDAI provides a reliable picture of systemic involvement in primary SS.

Comparison of the Birmingham Vasculitis Activity Score and the Five-Factor Score to Assess Survival in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Study of 550 Patients From Spain (REVAS Registry).

OBJECTIVE: To compare the accuracy of the Birmingham Vasculitis Activity Score (BVAS), version 3, and the Five Factor Score (FFS), version 1996 and version 2009, to assess survival in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: A total of 550 patients with AAV (41.1% with granulomatosis with polyangiitis, 37.3% with microscopic polyangiitis, and 21.6% with eosinophilic granulomatosis with polyangiitis), diagnosed between 1990 and 2016, were analyzed. Receiver operating characteristic (ROC) curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores. RESULTS: Overall mortality was 33.1%. The mean ± SD BVAS at diagnosis was 17.96 ± 7.82 and was significantly higher in nonsurvivors than in survivors (mean ± SD 20.0 ± 8.14 versus 16.95 ± 7.47, respectively; P < 0.001). The mean ± SD 1996 FFS and 2009 FFS were 0.81 ± 0.94 and 1.47 ± 1.16, respectively, and were significantly higher in nonsurvivors than in survivors (mean ± SD 1996 FFS 1.17 ± 1.07 versus 0.63 ± 0.81 [P < 0.001] and 2009 FFS 2.13 ± 1.09 versus 1.15 ± 1.05 [P < 0.001], respectively). Mortality rates increased according to the different 1996 FFS and 2009 FFS categories. In multivariate analysis, BVAS, 1996 FFS, and 2009 FFS were significantly related to death (P = 0.007, P = 0.020, P < 0.001, respectively), but the stronger predictor was the 2009 FFS (hazard ratio 2.9 [95% confidence interval 2.4-3.6]). When the accuracy of BVAS, 1996 FFS, and 2009 FFS to predict survival was compared in the global cohort, ROC analysis yielded area under the curve values of 0.60, 0.65, and 0.74, respectively, indicating that 2009 FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001 and when assessing the 1-year, 5-year, and long-term mortality. Correlation among BVAS and 1996 FFS was modest (r = 0.49; P < 0.001) but higher than between BVAS and the 2009 FFS (r = 0.28; P < 0.001). CONCLUSION: BVAS and FFS are useful to predict survival in AAV, but the 2009 FFS has the best prognostic accuracy at any point of the disease course.

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) in a man with a diagnosis of X-linked reticulate pigmentary disorder (PDR).

Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare syndrome characterized by episodes of intestinal suboclusion caused by intestinal stenosis with superficial ulceration. Histological findings in the cases described in the literature are similar, even though they are not specific. The cause of the syndrome is as yet unknown. We report on the case of a 25-year-old male with a protein losing enteropathy (PLE) in the context of the CMUSE syndrome. At a later date the patient was also diagnosed with an X-linked recessive reticulate pigmentary disorder (PDR). The clinical features and tests which led to the diagnosis are described. The reported cases of CMUSE and of the gastrointestinal symptoms in the three families with PDR are reviewed in order to search for an association between these two entities. To date, there is no evidence to ascertain whether these two rare syndromes observed in the same patient are related or coincidental.

Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis.

OBJECTIVE: To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model. PATIENTS AND METHODS: The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017. RESULTS: The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (P<.001), mixed microbiological infections (P=.02), and more than 1 infection (P=.01) and glucocorticoid monotherapy (P=.02). According to univariate analyses, platelets of less than 100,000/mm3 (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death. CONCLUSION: The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.